Process for preparing levobupivacaine and analogues thereof

ABSTRACT

A process for preparing levobupivacaine, racemic bupivacaine or another N-alkyl analogue thereof, comprises chlorinating pipecolic acid hydrochloride, amidation of the resultant pipecolyl chloride hydrochloride in solvent, without isolation, with 2,6-dimethylaniline, and alkylation of the resultant pipecolic acid 2,6-xylidide. Alternatively, the alkylation may be followed by the amidation.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a 371 of International Application No.PCT/GB95/02514 filed Oct. 23, 1995.

FIELD OF THE INVENTION

This invention relates to a novel process for the manufacture of racemicbupivacaine or levobupivacaine, and analogues thereof, from pipecolicacid.

BACKGROUND TO THE INVENTION

Bupivacaine (formula I in Scheme 1) and ropivacaine are well-known localanaesthetics. They are described in U.S. Pat. No. 4,695,576,GB-A-1166802, and PCT/NO83/00029. The corresponding N-methyl andN-cyclopropyl compounds also have such activity. However, the productionof such material on a large scale, from pipecolic acid, suffers fromvarious difficulties.

Phosphorus pentachloride has been used as a chlorinating agent. On alarge scale, its use is problematic, in that. PCl₅ is liable to reactwith atmospheric moisture, and to generate waste whose separation fromthe acid chloride intermediate (II) is difficult. Furthermore, thephosphate waste streams which are generated are difficult to treat orotherwise discard.

The use of acetyl chloride as the process solvent for the production ofthe acid chloride (II) poses similar difficulties.

Whereas isolation of the intermediate acid chloride (II) as described inthe art can be carried out on a laboratory scale, its isolation on thelarger scale is impractical. This is due to the fact that theintermediate (II) is a very labile substance and may decompose uponexposure to atmospheric moisture.

Washing of the isolated acid chloride (II) with commercial gradeacetone, as described in the art, will lead to its decomposition, ascommercial acetone usually contains some water.

Reaction of the acid chloride (II) with 2,6-dimethylaniline in a mixtureof acetone and N-methylpyrrolidone (NMP), as advocated in the art, leadsto the formation of pipecolic acid 2,6-xylidide (III) which is difficultto isolate from the reaction medium.

Alkylation of the intermediate (III) with 1-bromobutane and potassiumcarbonate in n-butanol affords comparatively poor yield of the desiredbupivacaine, since the reaction proceeds very slowly and usually doesnot go to completion.

SUMMARY OF THE INVENTION

The present invention describes a practical and streamlined one-potprocess which is both economical and viable for scale-up. Furthermore,this invention may be used to manufacture racemic bupivacaine,levobupivacaine, or any corresponding N-alkylated material such asropivacaine (Pr rather than Bu) in racemic or enantiomeric form.

According to this invention, pipecolic acid is initially reacted withhydrogen chloride in a suitable solvent, furnishing pipecolic acidhydrochloride salt.

This compound is not isolated from the reaction medium but is directlytreated with thionyl chloride, whereupon pipecolic acid chloridehydrochloride (II) is produced. Other chlorinating agents may be used,provided that they do not contain phosphorus, e.g. oxalyl chloride.

Again, this intermediate is not isolated and is conveniently treatedwith (2 equivalents of) 2,6-dimethylaniline. This operation generatesthe HCl salt of the intermediate (III) which is later isolated, afterwork-up. By controlling the pH, the free base can be obtained,essentially uncontaminated with 2,6-dimethylaniline (which is releasedas the pH is increased).

Alkylation of the free base of intermediate (III) is carried out with analkylating agent such as 1-bromobutane in a suitable solvent such asacetonitrile (ACN) or advantageously in dimethylformamide (DMF) in thepresence of a suitable base such as potassium carbonate. The reactionproceeds rapidly, and the resulting free base of, say, bupivacaine isisolated after removal of the solvent.

The free base may then be dissolved in a suitable solvent such asisopropanol and treated with hydrogen chloride, affording the HCl saltof, say, bupivacaine which is recovered by filtration (see Scheme 1).

It appears that no significant racemisation occurs during this novelprocess. Therefore, for example, by using enantiomerically pure(S)-pipecolic acid in this process, levobupivacaine can be produced.

DESCRIPTION OF THE INVENTION

The process of the invention is carried out by the steps describedabove. If desired, alkylation may precede amidation. An alternativepreparation of the free base (III) is described in our InternationalPatent Application No. PCT/GB95/02385.

The following Examples illustrate the invention.

EXAMPLE 1 PIPECOLIC ACID 2,6-XYLIDIDE

Pipecolic acid (130 g) was suspended in 2 l toluene and was stirred atambient temperature. Hydrogen chloride (40 g) was added slowly during 30minutes.

The mixture was heated to 55° C. and 1 g of DMF was added, followed bythe addition of thionyl chloride (120 g) during 1.5 hours. The stirringat this temperature was continued until evolution of gases ceased.

2,6-Dimethylaniline (242 g) in toluene (250 ml) was added to the mixtureat such a rate that the temperature of the mixture was maintained below60° C. After 2 hours, the mixture was filtered and washed with toluene(200 ml). The resulting solid was dissolved in water (2.5 l) and wastreated with aqueous NaOH until its pH was raised to 4.5-5.5. Theliberated 2,6-dimethylaniline was removed by extraction with toluene.

The pH of the aqueous layer was raised still further, to 11-12,whereupon pipecolic acid-2,6-xylidide (III) was liberated. Thisintermediate was extracted with toluene and was obtained after removalof the solvent as a crystalline solid (151 g, 65% of theory).

Example 2 N-n-Butylpipecolic Acid 2,6-Xylidide

1-Bromobutane (90 g) was added to a suspension of pipecolicacid-2,6-xylidide (140 g) and a potassium carbonate (100 g) in DMF (330ml). The mixture was stirred and heated at 80° C. for 90 minutes andthen was allowed to cool to 35° C. The solids were filtered off and theDMF solution was added to cold water (1.5 l) whereuponN-n-butylpipecolic acid 2,6-xylidide precipitated as a pale cream solid(159 g, 92% theory).

Example 3 N-n-Butylpipecolic Acid 2,6-Xylidide HCl Salt

Hydrogen chloride (25 g) was introduced slowly into a stirred solutionof N-n-butylpipecolic acid 2,6-xylidide (145 g) in isopropanol (250 ml)at ambient temperature. The resulting white product was filtered off,washed with isopropanol and dried under vacuum to constant weight (161g, 99% theory).

In order to prepare levobupivacaine, by the process of the presentinvention, a first route involves preparing and then resolving racemicbupivacaine. A racemisation process is described in International PatentApplication No. PCT/GB95/02247. A second route involves starting fromthe appropriate pipecolate enantiomer. ##STR1##

We claim:
 1. A process for preparing a1-alkyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide, as the free baseor a salt thereof, which comprises the steps of: (i) reacting pipecolicacid hydrochloride with an excess of a P-free chlorinating agent in asolvent, and distilling off said chlorinating agent;(ii) reacting theresultant pipecolyl chloride hydrochloride in solvent, withoutisolation, with excess 2,6-dimethylaniline; (iii) raising the pH toseparate the resultant pipecolic acid 2,6-xylidide from excess2,6-dimethylaniline; (iv) alkylating said 2,6-xylidide; and, (v)isolating the product from the reaction mixture.
 2. The process,according to claim 1, wherein the solvent in steps (i) and (ii) isselected from the group consisting of a hydrocarbon, halogenatedhydrocarbon and ether.
 3. The process, according to claim 2, wherein thesolvent is selected from the group consisting of toluene, methyltert-butyl ether and tetrahydrofuran.
 4. The process, according to claim1, wherein the alkylation is conducted in a solvent that solvates K₂ CO₃and is water-miscible.
 5. The process, according to claim 4, whereinsaid water-miscible solvent is DMF or acetonitrile.
 6. The process,according to claim 1, whereby (S)-pipecolic acid is converted tolevobupivacaine.
 7. The process, according to claim 1, wherein theproduct is racemic bupivacaine.
 8. The process, according to claim 1,wherein the product is1-propyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide, in racemic oroptically-enriched form.
 9. The process, according to claim 1, whereinthe amidation comprises using 2 equivalents of 2,6-dimethylaniline. 10.The process, according to claim 1, wherein said chlorinating agent isSOCl₂ or oxalyl chloride.
 11. The process, according to claim 1, whereinsaid chlorinating agent is distilled off with HCl.
 12. The process,according to claim 1, wherein step (iv) is followed by conversion of theresultant free base product to a salt thereof and then proceeding tostep (v).